Diffusion tensor imaging (DTI) characterization of white matter microstructure abnormalities in autism spectrum disorder (ASD) generally demonstrate decreased water diffusion anisotropy in frontal cortex and corpus callosum, consistent with frontal disconnectivity theories of autism. However, DTI findings in ASD show considerable heterogeneity and little is known about differential involvement of the intracellular and extracellular compartments or mechanisms underlying changes in water diffusion that limit the extent to which DTI can be used to characterize developmental processes in ASD. Diffusion tensor 1H MRSI (DTSI) can provide unique information on intracellular properties, such as viscosity, cell swelling, restriction in subcellular structures and cytoplasmic streaming, that may help to characterize possible inflammatory processes in autism. All human studies so far have used single voxel localization method (e.g. Posse et al 1993a, Ellegood et al 2005 and 2006, Upadhyay et al 2007) due to overwhelming motion sensitivity of conventional MRSI techniques (Posse et al. 1993b), which do not allow mapping of metabolite diffusion across extended brain areas hypothesized to be involved in autism. The objective of this proposal is to develop single-shot diffusion sensitive MRSI to dramatically reduce motion sensitivity, and to show feasibility of volumetric mapping of metabolite diffusion in healthy adults and children with ASD using a clinical 3 Tesla whole body scanner. The specific aims of this proposal are: 1. to develop DTSI with single-shot 2D spatial-spectral encoding and correction for macroscopic movement using (a) compressed sensing combined with parallel imaging and (b) SURE-SENSE reconstruction to further increase spatial resolution. An exploratory aim is to investigate feasibility of single-shot 3D spatial- spectral encoding using 2D compressed sensing combined with parallel imaging. 2. To validate DTSI in phantoms and healthy adult brain at 3 T The working hypothesis is that single-shot DTSI can map the diffusion tensors of tissue water, Choline, Creatine and NAA with sensitivity per unit time and unit volume that is comparable to single-voxel diffusion tensor spectroscopy. 3. To demonstrate feasibility of DTSI in the brains of 3 year old children with ASD at 3 T The working hypothesis is that DTSI will detect regional decreases in diffusion anisotropy of NAA in ASD. An exploratory aim is to determine whether NAA diffusion anisotropy in these regions will be more strongly decreased in comparison to diffusion anisotropy of tissue water measured with DTSI and DTI, implicating intracellular inflammatory processes. This DTSI methodology has the potential to enhance the scope of imaging studies of ASD by helping to clarify mechanisms underlying abnormal brain development in ASD through characterizing the involvement of intracellular compartments and in relationship to the time course of disease progression. Applications to other organs and muscle are also foreseeable. PUBLIC HEALTH RELEVANCE: The objective of this research is to develop a novel ultra high-speed MR spectroscopic imaging technique for mapping the diffusion tensors of brain metabolites using a 3 Tesla whole body MRI scanner. The goal of this research is to enhance the specificity of the widely used diffusion tensor imaging (DTI) method for clinical studies of neurological diseases by measuring metabolite mobility in the intracellular compartments and to relate this measure to the time course of disease progression. The specific aims of this application are (a) Develop single-shot diffusion sensitive 1H MR spectroscopic imaging using a combination of compressed sensing and parallel imaging reconstruction at 3 T, (b) validate this methodology in human brain at 3 T, and (c) demonstrate the feasibility of DTSI in the brains of 3 year old children with Autism Spectrum Disorder at 3 T. This DTSI methodology has the potential to enhance the scope of imaging studies of ASD by helping to clarify mechanisms underlying abnormal brain development in ASD through characterizing the involvement of intracellular compartments and in relationship to the time course of disease progression. Applications to other organs and muscle are also foreseeable.